Review
Marine Microalgal Products with Activities against Age-Related
Cardiovascular Diseases
Nova Yurika 1,2,†, Eleonora Montuori 2,3,† and Chiara Lauritano 2,*
1 Marine Biology Research Group, Ghent University, Krijgslaan 281, B-9000 Gent, Belgium;
yurika.nova@ugent.be
2 Ecosustainable Marine Biotechnology, Stazione Zoologica Anton Dohrn, Via Acton 55, 80133 Napoli, Italy;
eleonora.montuori@studenti.unime.it
3 Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina,
Viale F. Stagno d’Alcontres 31, 98166 Messina, Italy
* Correspondence: chiara.lauritano@szn.it; Tel.: +39-0815833221
† These authors contributed equally to this work.
Abstract: Heart disease is one of the leading causes of death worldwide, and it is estimated that
17.9 million people die of it each year. The risk factors for cardiovascular diseases are attributable to
an unhealthy and sedentary lifestyle, poor nutrition, stress, genetic predisposition, diabetes, obesity,
and aging. Marine microalgae have been the subject of numerous studies for their potential activity
against several human diseases. They produce a plethora of primary and secondary metabolites such
as essential nutrients, vitamins, pigments, and omega-3 fatty acid. Many of these molecules have
antioxidant properties and have been shown to play a role in the prevention of heart diseases. The
aim of this review is to summarize recent studies on the discovery of marine microalgal compounds
and bioactivities for cardiovascular diseases, including in vitro and in vivo studies, showing and
discussing recent discoveries and trends. The most promising results were found for microalgal
polysaccharides, peptides and carotenoids. In conclusion, the overall data summarized here show
that microalgae-based supplementation has the potential to improve age-related cardiovascular
diseases and we expect more clinical studies in the future.
Keywords: cardiovascular diseases; marine microalgae; antioxidants; age-related diseases; bioactive
compounds; marine natural products
Citation: Yurika, N.; Montuori, E.;
Lauritano, C. Marine Microalgal
Products with Activities against
Age-Related Cardiovascular Diseases.
Mar. Drugs 2024, 22, 229. https://
doi.org/10.3390/md22050229
Academic Editors: Javier
Ávila-Román, Giuseppina
Tommonaro and Annabella Tramice
Received: 28 March 2024
Revised: 3 May 2024
Accepted: 15 May 2024
Published: 17 May 2024
Copyright: © 2024 by the authors.
Licensee MDPI, Basel, Switzerland.
This article is an open access article
distributed under the terms and
conditions of the Creative Commons
Attribution (CC BY) license (https://
creativecommons.org/licenses/by/
4.0/).
1. Introduction
Marine microalgae have been the subject of numerous studies for their potential ac-
tivities against several human diseases [1,2]. Microalgae have attracted a lot of attention
in recent years owing to their biodiversity in terms of species, adapted to live in different
environments, and in terms of chemical diversity, ranging from lipids and carbohydrates
to complex polyketides. In addition, their use has been considered eco-sustainable and
eco-friendly owing to their high growth rates and the possibility of culturing these both
indoors and outdoors at an industrial scale. Various studies have also shown that these
microorganisms are a promising source of beneficial nutrients for heart health. They pro-
duce a plethora of metabolites such as essential nutrients, vitamins, pigments, omega-3
fatty acid, and several antioxidant molecules which may play a role in the prevention
of heart disease [3,4]. In particular, the n-3 long-chain polyunsaturated fatty acids (n-3
LC-PUFAs), such as eicosapentaenoic (EPA) and docosahexaenoic (DHA) acids, are known
for their beneficial effects on the cardiovascular system [5,6] and to have protective effects
against atherosclerotic, arrhythmic and thrombotic diseases [7,8]. These fatty acids have
been reported to reduce cholesterol levels in the blood, lower blood pressure, and reduce
inflammation [5,6]. The European Food Safety Authority (EFSA) recommends an intake
of 250 mg for EPA plus DHA for adults, 100 mg DHA for infants (>6 months) and young
Mar. Drugs 2024, 22, 229. https://doi.org/10.3390/md22050229 https://www.mdpi.com/journal/marinedrugsMar. Drugs 2024, 22, 229 2 of 15
children <24 months, and to increase the dose during pregnancy and lactation [9]. Further-
more, marine microalgae also contain other antioxidant molecules, such as pigments [10]
and vitamins, like vitamin E, vitamin A and vitamin of complex B. These antioxidants
have been reported to play a significant role in the prevention of cardiovascular diseases
(CVD) [11,12]. For instance, it has been shown that pre-treatments with antioxidants, such
as vitamins C and E, can mitigate endothelial dysfunction due to high-fat meals [13].
According to the World Health Organization (WHO), heart disease is one of the leading
causes of death worldwide (https://www.who.int/health-topics/cardiovascular-diseases/
#tab=tab_1 accessed on 29 January 2024), with about 17.9 million deaths globally each year.
Cardiovascular diseases are the most prevalent age-related diseases [14,15]. As the pace
of population aging around the world is increasing dramatically, old population presents
one of the greatest challenges for the social and health care systems worldwide, especially
in low-income and middle-income countries [16]. For older patients, hypertension, hyper-
lipidemia and diabetes are also frequent negatively influencing cardiovascular events [17].
Overall, cardiovascular disease prevention in older adults should be established based on
the individuals, based on their estimated life expectancy, time to benefit, comorbidities,
and preferences (e.g., more plant-based and low-fat diet, exercise when possible, quitting
smoking, etc.).
The risk factors for cardiovascular diseases are mainly attributable to an unhealthy
lifestyle, poor nutrition, sedentary lifestyle, stress, genetic predisposition, diabetes, obesity
and aging (Figure 1) [18]. As reported in Izzo et al. [19], both age and gender are risk
factors. Older females are more susceptible to cardiovascular disease compared to men
of the same age. In both cases, in both men and women, these diseases are related to
a decrease in sex hormones [19,20]. Possible women-specific risk factors that have been
considered include gestational diabetes mellitus, pregnancy-induced hypertension, and
preeclampsia, as well as reproductive endocrine disorders, including polycystic ovary
syndrome and menopause [20]. CVD risk factors are highly prevalent in some countries
and vary according to socioeconomic, gender, and educational levels [18]. In Pakistan,
smoking (46%), family history (43%), hypertension (37%), dyslipidemia (33%), diabetes
mellitus (18%) and overweight (63.3%) are the most common risk factors found in CVD
patients under 45 years of age [21]. In the UK, the rate of hypertension has been reported
as the highest risk, approximately 65%, followed by smoking (44.2%), high cholesterol
(38.7%), diabetes (12%), overweight (5.13%), male gender (4.6%), and female gender (5.6%).
In adults, metabolic risk factors tend to increase with age [22]. Additional factors, including
frailty, obesity, and diabetes could complicate and enhance CVD risk factors amongst
the elderly [23,24]. With advancing age, the heart undergoes structural and functional
changes that make it more susceptible to pathologies such as heart failure, arrhythmia
and atherosclerosis [25]. The onset of various health issues is related to the subsequent
contribution of damages to the blood vessels and the heart itself. Obesity can cause an
increase in blood cholesterol, which leads to a greater predisposition to the development of
atherosclerotic diseases.
In this review, we reported marine microalgal compounds with beneficial and preven-
tive activities against heart diseases related to aging. When available, we also discussed
doses and mechanisms of action for both in vitro and in vivo studies. We showed that
the most bioactive molecules from microalgae reported for CVDs were polysaccharides,
peptides, carotenoids and lipids.Mar. Drugs 2024, 22, 229 Mar. Drugs 2024, 22, 229 3 of 15
3 of 15
Figure 1. A schematic representation of principal risk factors of cardiovascular diseases and main
Figure 1. A schematic representation of principal risk factors of cardiovascular diseases and main
microalgae which have shown potential beneficial activities.
microalgae which have shown potential beneficial activities.
2. Polysaccharides
2. Polysaccharides
Several studies have reported the potential of polysaccharides (PSs) to improve en-
Several studies have reported the potential of polysaccharides (PSs) to improve en-
dothelial dysfunction, defined as functional, structural, and communication changes be-
dothelial dysfunction, defined as functional, structural, and communication changes be-
tween the vascular endothelium and muscle cells [26]. For example, Levy-Ontman et al. in
tween the vascular endothelium and muscle cells [26]. For example, Levy-Ontman et al.
2017 [27] evaluated the anti-inflammatory and vasodilation properties of polysaccharides
in 2017 [27] evaluated the anti-inflammatory and vasodilation properties of polysaccha-
produced by Porphyridium sp. using human coronary artery endothelial cells (HCAECs).rides produced by Porphyridium sp. using human coronary artery endothelial cellsMar. Drugs 2024, 22, 229 4 of 15
The authors showed that polysaccharides were able to attenuate inflammatory processes by
interfering with tumor necrosis factor-alpha (TNF-α)-induced inflammation. In cells pre-
treated with polysaccharides, there was an up-regulation of adhesion molecule 1 (ICAM-1)
and vascular cell adhesion molecule 1 (VCAM-1), nuclear factor kappa-B (NF-kB) transloca-
tion, and attenuated inhibitor of nuclear factor kappa B (IκB) degradation. Polysaccharides
improved endothelial function as measured by increased nitric oxide NO formation and
decreased endothelin 1 (ET-1) protein expression [27]. Hamias et al. in 2018 [28] studied
the ability of polysaccharides (PSs) from Porphyridium sp. to improve endothelial state
and found that PSs attenuated inflammatory atherosclerotic pathways up-regulated by
Angiotensin II (Ang II). When HCAECs were pre-treated with PSs (500 µg/mL) under Ang
II induction, PSs were able to down-regulate the NF-kB activation and suppress adhesion
molecule ICAM-1 and VCAM-1 up-regulation in a dose-dependent manner. Furthermore,
polysaccharides enhanced nitric oxide (NO) and endothelial nitric oxide synthase (eNOS)
production, and reduced ET-1 expression levels [28].
3. Peptides
3.1. In Vitro
In addition to polysaccharides, peptides can counteract the pathological processes
by mimicking the function of mediators or modulating the activities and expression of
mediators involved in hypertension, hypercholesterolemia, diabetes, inflammation and
oxidative stress [29]. Lin et al. [30] studied Isochrysis zhanjiangensis, which was suggested
to inhibit vascular injury and angiogenesis, and to have a protective effect on CVDs.
They characterized the production and the activity of an octapeptide (ICE) isolated from
I. zhanjiangensis, demonstrating that ICE was able to decrease ROS production in lipopolysac-
charide (LPS)-induced HUVECs (concentrations of ICE 1, 10, 20, and 50 µM). The peptide
could reduce cell damage by increasing the expression of antioxidant enzymes, such as the
antioxidant enzymes superoxide dismutase (SOD), glutathione peroxidase-1 (GPX), and
haem oxygenase 1 (HO-1). In addition, it also inhibited pro-inflammatory mediators tumor
necrosis factor (TNF)-α, cytokine interleukin-6 (IL-6), and ICAM-1 [30] (Table 1). Vo et al.
in 2013 [31] isolated two peptides with aminoacidic sequences of LDAVNR for peptide
1 and MMLDF for peptide 2 from the peptidic hydrolysates of Spirulina maxima. These
peptides showed anti-inflammatory properties in histamine-induced EA.hy926 endothe-
lial cells (used for cardiovascular disease research) with a decrease in interleukin (IL)-8
expression, measured by the ELISA assay. It is known that endothelial inflammation is a
risk factor for atherosclerosis and the authors suggested these two peptides for possible
anti-atherosclerotic activity [31].
Jiang et al. in 2021 [32] suggested that microalgal compounds may have great potential
as a healthier anti-hypertensive treatment substitution to conventional anti-hypertensive
drugs causing side effects. Hypertension, a risk factor for the development of CVDs, con-
sists of a sustained increase in arterial pressure above 140/90 mm Hg [33]. In particular,
the authors showed that peptides from microalgae are promising angiotensin-converting
enzyme (ACE) inhibitors (Table 1). Renin–angiotensin–aldosterone system (RAAS) hy-
peractivity is involved in the progression of vascular disease. The key effector peptide
of the RAAS, angiotensin II (Ang II), is generated by angiotensin I through endothelial
angiotensin-converting enzyme (ACE). Inhibition of RAAS is recommended for managing
most cardiovascular diseases, particularly hypertension, heart failure, acute myocardial
infarction, and stroke [34]. ACE inhibitors and angiotensin receptor blockers (ARBs) are
commonly prescribed medication for primary hypertension [35] and other chronic con-
ditions, including heart failure, by reducing systolic function. Chen et al. in 2020 [36]
purified and identified a peptide (PIZ protein hydrolysate) produced by Isochrysis zhan-
jiangensis that was able to inhibit ACE. The ACE activity calculated from the amount of
hippuric acid liberated from hippuryl-His-Leu (HHL) showed that PIZ acts as a mixed
non-competitive inhibitor of ACE at an IC50 value of 61.38 µM. Pretreatment with PIZ
10 µM for 24 h on human umbilical vein endothelial cells (HUVECs) inhibited the NF-κBMar. Drugs 2024, 22, 229 5 of 15
pathway by protecting inhibitor IκBαdegradation and down-regulating NF-κB expression.
In addition, they showed that PIZ had modest ACE inhibitory effects due to its ability
to reduce inflammatory cytokine expression (NO, COX-2, and ICAM-1) and block the
production of ET-1. ICAM-1 and MCP-1 levels were significantly suppressed by PIZ in
a dose-dependent manner. Cell treatment with PIZ 10 µM decreased the expression lev-
els of inflammatory cytokines COX-2 and slightly inhibited iNOS and ET-1 production,
thereby improving endothelial dysfunction, reducing oxidative stress, and decreasing the
risk of hypertension [36]. Samarakoon et al. [37] showed that pepsin hydrolysate from
Nannochloropsis oculate exhibited ACE inhibitory activity. They demonstrated that the
IC50 values of purified ACE inhibitory peptides were 123 µM and 173 µM and identified
Gly-Met-Asn-Asn-Leu-Thr-Pro (GMNNLTP; MW, 728 Da) and Leu-Glu-Gln (LEQ; MW,
369 Da) as novel peptides, respectively [37]. Wu et al. in 2015 [38] reported that a puri-
fied peptide (Tyr-Met-Gly-Leu-Asp-Leu-Lys) from Isochrysis galbana showed potent ACE
inhibitory activity with an IC50 of 36.1 µM. In 2017, Heo et al. [39] conducted a study to
produce an ACE inhibitory peptide from marine Spirulina sp. The ACE inhibitory peptide
(Thr-Met-Glu-Pro-Gly-Lys-Pro) showed the strongest ACE activity at an IC50 value of
0.3 mg/mL. In addition, the human umbilical vein endothelial cells (HUVECs) were treated
for 1 h with aliquots of purified peptide (62.5, 125 and 250 µM) and subsequently incubated
for 24 h with Ang II (1 µM). They showed that ACE inhibitory peptide inhibited NO and
ROS generation, and suppressed the expression of inducible nitric oxide synthase (iNOS)
and ET-1 [39].
Cunha et al. in 2022 [40] also showed that water-soluble hydrolysates rich in pro-
teins/peptides from the microalgae Chlorella vulgaris had anti-hypertensive potential by
measuring the percentage inhibition of the ACE enzyme (IC50: 286 µg protein/mL) [40].
Recently, Pei et al. [41] showed that nonapeptide ETT (Glu-Met-Phe-Gly-Thr-Ser-Ser-Glu-
Thr) from Isochrysis zhanjiangensis showed excellent effects in regulating hypertension by
inhibiting ROS up-regulation of oxidized low-density lipoprotein receptor-1 (LOX-1) and
ROS levels in Ang II-induced human umbilical vein endothelial cells (HUVECs). In addi-
tion, ETT inhibited the expression of various inflammatory mediators and the expression
of related cytokines (IL-1β, IL-8, TNF-α, iNOS, COX-2, ET-1, AT-1) as well as cell adhesion
molecules (ICAM-1 and VCAM-1) in a dose-dependent manner (10, 50, and 100 µM) [41].
Alzahrani et al. in 2018 [42] screened the anti-hypertension activities of Nitzschia laevis
in vitro. The author showed that trypsin hydrolysates from this species had antagonist
effects toward the ACE enzyme (IC50 1.63 ± 0.01 mg/mL), higher than that of Spirulina
and Chlorella [42]. Verspreet et al. [43] screened five microalgae (i.e., Chlamydomonas nivalis,
Porphyridium purpureum, Chlorella vulgaris, Nannochloropsis gaditana, and Scenedesmus sp.)
with respect to their ability to inhibit ACE by measuring the activity owing to an ACE-1
inhibition kit. The ACE inhibition bioassay showed that all microalgae tested inhibited
ACE by 73.4–87.1% when tested at a concentration of 1 mg/mL [43].
3.2. In Vivo
Regarding in vivo experiments, the activities found were mainly related to anti-
hypertension. Ko et al. [44] found that a purified peptide (Val–Glu–Gly–Tyr) from marine
Chlorella ellipsoidea acted as a competitive inhibitor against ACE with an IC50 value of
128.4 µM. Furthermore, they tested the anti-hypertensive effects of the purified peptide by
measuring the change in systolic blood pressure at 2, 4, 6 and 8 h after oral administration
of the peptide (10 mg/kg of body weight) and showed that purified peptide was able to
significantly decrease systolic blood pressure in rats [44].
Barkia et al. in 2019 [45] screened six strains of marine diatoms and found that papain
hydrolysates had ACE inhibitory activity in vitro (2 mg/mL), with the highest activity
obtained from Bellerochea malleus. Furthermore, in vivo assays showed that Bellerochea
malleus hydrolysates reduced systolic and diastolic blood pressure in male spontaneously
hypertensive rats after 5 days of hydrolysate treatment at doses of 75 and 100 mg/kg
body weight [45]. Hayes et al. in 2023 [46] studied hydrolysate and bioactive peptidesMar. Drugs 2024, 22, 229 6 of 15
from the red microalga Porphyridium sp., namely, GVDYVRFF, AIPAAPAAPAGPKLY,
and LIHADPPGVGL, and assessed the anti-hypertensive activity using spontaneously
hypertensive rats. The Porphyridium sp. hydrolysate was also included in a food carrier
(jelly candies; 0.5 g of the hydrolysate). Hydrolysate and hydrolysate–jelly candies reduced
systolic blood pressure by−1.54 mm Hg and−6.17 mm Hg, respectively, while Captopril®
reduced systolic blood pressure by−18.21 mm Hg after 24 h [46].
4. Carotenoids
4.1. In Vitro
Microalgae are known to produce a variety of pigments with various color shades
and biological activities, including carotenoids [3,12]. Zuluaga et al. in 2018 [47] reported
astaxanthin protective actions against ischemia and reperfusion (I/R) injury. Astaxanthin
also ameliorates myocardial cell oxidative stress injury [47]. Astaxanthin from the freshwa-
ter microalga Haematococcus pluvialis has also been shown to prevent oxidative stress on
human endothelial cells (HUVECs) without toxicity up to a dose of 10 µg/mL [48].
4.2. In Vivo
El-baz et al. in 2018 [49] demonstrated that β-carotene rich Dunaliella salina carotenoid
fraction (250 g/kg) as well as the whole biomass (250 mg/kg) had protective potentials
against cardiac disfunction in a group of rats injected with D-galactose (200 mg/kg).
Dunaliella salina β-carotene and biomass exhibited potent antioxidant activity and signifi-
cant reducing capacity of homocysteine, IL-6 and iNOS. In another study, El-Baz et al. [50]
examined the effects of zeaxanthin heneicosylate (ZH) isolated from Dunaliella salina on
cardiac dysfunction. The study was performed in vivo in rats, by injecting D-galactose
in rats for 8 weeks following orally treated with ZH (250 µg/kg) for a period of 28 days.
ZH improved cardiac aging manifestation, including irregular heartbeat and increased
NF-κB. ZH injected rats ameliorated NF-κB and restored superoxide dismutase (SOD).
SOD is an antioxidant enzyme that has been shown to protect the heart against oxida-
tive stress, and ischemic damage, and hypertrophy after myocardial infarction [51]. Oral
administration of ZH up-regulated retinoic acid receptor alpha (RAR-α) gene expression
in cardiac tissue. RAR-αplays important roles in cardiac regeneration after myocardial
infarction. Depletion of RA pathway leads to cardiomyocyte apoptosis after myocardial
infarction [52]. El-Baz et al. [53] conducted a study on the carotenoid rich fraction of the
microalgae Dunaliella salina activity against inflammation-associated cardiac dysfunction in
cardiac-obese rats induced by high fat diet, demonstrating that the carotenoid rich fraction
increased adiponectin and glucagon serum level. The histopathological examination of
rat treated with the carotenoid rich fraction showed the absence of fibrosis and severe
congestion in the myocardial blood vessels [53].
5. Lipids and Other Bioactive Extracts and Molecules
In addition to polysaccharides, peptides and pigments, other molecules from mi-
croalgae have shown promising results. In particular, Dahli et al. [54] demonstrated
that lyso-diacylglyceryltrimethylhomoserine (lyso-DGTS) isolated from Nannochloropsis
sp. ethanolic extract might be useful for the prevention of atherosclerotic risk factors by
showing increased activities of recombinant paraoxonase 1 (rePON1) lactonase [54].
A mixture of omega-3 polyunsaturated fatty acids (35%) from Schizochytrium sp., extra
virgin olive oil (75%) and algae oil (25%) was reported to activate the phosphoinositide
3 kinase (PI3K/Akt) pathway that is known to repair vascular endothelium. Aortic rings
from old rats treated with the oil mixture (2.5 mL/kg) showed a decreased response to the
vasoconstrictor Ang II [55]. Haimeur et al. [56] assessed the effects of two n-3 PUFA from
freeze-dried Odontella aurita on risk factors for CVDs. A rat group fed with the high-fat
diet supplemented with Odontella aurita displayed a significantly lower body weight and
reduced insulinemia, as well as a reduced serum lipid level, reduced platelet aggregation
and oxidative status induced by high fat intake. The authors reported that Odontella auritaMar. Drugs 2024, 22, 229 7 of 15
was more effective than the fish oil in reducing the hepatic triacyglycerol levels and in
preventing high-fat diet-induced steatosis [56].
Dudek et al. [57] summarized, in a review, the beneficial role of dietary silicon in the
prevention of age-related diseases. Vide et al. [58] reported the effects of Spirulina and
dietary silicon-enriched Spirulina (SES) on atherosclerosis. Hamsters on a high-fat diet
were treated with Spirulina or SES at a dose 57 mg/kg body weight daily, corresponding to
0.57 mg of silicon/kg body weight. The results showed that in the SES group, there was a
reduction in inflammation by lowering the levels of TNF-α, IL-6, as well as a reduction in
the number of polymorphonuclear cells and prevention of the activity of NF-κB. Both SES
and Spirulina itself similarly protected against oxidative stress by reducing the activity of
nicotinamide adenine dinucleotide phosphate oxidase (NOX) and maintaining the activity
of the antioxidant SOD and glutathione peroxidase [58].
Quagliariello et al. in 2022 [59] reported that Spirulina platensis, Ganoderma lucidum
and Moringa oleifera were able to improve cardiac function by reducing inflammation and
cardiotoxicity induced by anthracyclines, adjuvant therapies for cancers. Female mice
were treated with doxorubicin (DOXO) or a combination of Spirulina, Ganoderma lucidum,
and Moringa oleifera (Singo). Following that, they analyzed the myocardial expressions of
nucleotide-binding domain, leucine-rich–containing family, pyrin domain-containing-3
(NLRP3), galectin-3 and calgranulin S100, and 13 cytokines through ELISA methods. The
authors also assessed myocardial fibrosis, necrosis, and hypertrophy through immuno-
histochemistry. In addition, they performed tests on human cardiomyocytes by exposing
them to DOXO (200 nM) alone or in combination with Singo (at 10, 25 and 50 µg/mL) for
24 and 48 h. The results showed that Singo reduced NLRP3 and p65/NF-kB levels in human
cardiomyocytes exposed to Singo at 10, 15 and 50 µg/mL and reduced cytokine levels
(the concentration of Singo was 25 µg/mL). Immunohistochemistry analysis indicated that
Singo (at 12 mg/kg) reduced fibrosis and hypertrophy in the myocardial tissues of mice
during exposure to DOXO [59].
Umei et al. in 2022 [60] demonstrated that oral administration of Euglena gracilis was
beneficial to improve cardiac function in a mice model of isoproterenol-induced heart
failure. A group of mice were injected with isoproterenol (ISO) (20 mg/kg/day) for
7 days. They showed that oral administration of Euglena gracilis (2%), in combination with
an AIN93G diet, alleviated cardiac dysfunction [60]. Song et al. [51] tested Dunaliella salina’s
protective effects on myocardial ischemia/reperfusion injury (MIRI) in the Langendorff
perfused heart model in mice. The authors reported that D. salina (500 mg/kg) was able to
improve left ventricle function, reduce the rate of malignant arrhythmia and infarct size,
and increase the antioxidant superoxide dismutase. In a recent study published by Tsai
et al. in 2023 [61], D. salina was reported to have cardioprotective effects against myocardial
ischemia/reperfusion (I/R) injury. A group of rats was subjected to surgical procedures
for inducing myocardial I/R injury. D. salina extract treatment (0.1 mg/kg) was able to
decrease myocardial infarct size and attenuate the expressions of cyclooxygenase-2 (COX-2)
and the activity of STAT1, janus kinase 2 (JAK2), inhibitor of IκB, NF-κB [61]. Yang et al. [62]
showed that Chlorella pyrenoidosa was able to lower the blood pressure in rats fed a diet
containing N ω-nitro-L-arginine methyl ester hydrochloride (L-NAME), which induced
endothelial dysfunction (40 mg/kg). Rats consuming 4 and 8% Chlorella had significantly
lower ACE activity in the aorta and reduced TNF-αconcentrations in the aorta and heart.
Histopathological results showed that Chlorella consumption reduced the injury scale of
the coronary arteries, ventricles, and septum of the heart [62].
Clinical Studies
Recently, Sandgruber et al. [63] completed a clinical trial with 80 young and healthy
participants who consumed a smoothie enriched with either 15 g of Chlorella pyrenoidosa
dry weight (d.w.) or 15 g of Microchloropsis salina d.w. for 14 days. They demonstrated
that regular consumption of Chlorella pyrenoidosa ameliorated CVD factors such as total
cholesterol, LDL cholesterol, the LDL–cholesterol to HDL–cholesterol ratio, and non-HDLMar. Drugs 2024, 22, 229 8 of 15
cholesterol, possibly due to its rich vitamin D2 source. Microchloropsis salina improved the
fatty acid distribution in plasma lipids by increasing the LC n3 PUFA content and reducing
the n6/n3 PUFA ratio [63]. Clinical studies with Chlorella were also conducted by Shimada
et al. [64] with eighty subjects with systolic blood pressure of 130–159 mmHg or diastolic
blood pressure of 85–99 mmHg. The subjects took γ-Aminobutyric Acid (GABA)-rich
Chlorella (20 mg as γ-aminobutyric acid or placebo twice daily for 12 weeks) as a dietary
supplement. Systolic blood pressure decreased significantly compared with placebo, with
a higher reduction in the subjects with borderline hypertension than in the subjects with
high–normal blood pressure [64]. A randomized triple-blind placebo-controlled clinical
trial study conducted by Ghaem et al. [65] in 2021 involved 41 patients with hypertension
consuming a salad dressing containing 2 g of Spirulina platensis powder for two months. The
results showed that the Spirulina dressing significantly decreased systolic blood pressure,
diastolic blood pressure, serum triglyceride, total cholesterol, and low-density lipoprotein
(LDL) levels in comparison to placebo controls [65]. Bioactive compounds and extracts
from microalgae for CVDs are summarized in Table 1.
Table 1. The table reports marine microalgal bioactive compounds with potential beneficial activities
for cardiovascular diseases. Microalgae, activity observed, compound, concentration (Conc.) used,
and model are reported. Abbreviations: CVDs for cardiovascular diseases, DHA for Docosahexaenoic
acid, EPA for Eicosapentaenoic acid, EVOO for extra virgin olive oil, IC50 for inhibitory concentration
values, NLRP3 for NOD-, LRR- and pyrin domain-containing protein 3.
Microalgae Activity Observed Compound Conc. Model Reference
Polysaccharides
Porphyridium sp.
(Rhodophyta/Porphyridiophyceae)
Preserve
endothelial
function,
anti-inflammatory
Polysaccharides 50 µg/mL
In Vitro: Human
coronary artery
endothelial cells
(HCAECs)
[27]
Porphyridium sp.
(Rhodophyta/Porphyridiophyceae)
Preserve
endothelial
function, anti-
atherosclerosis
Polysaccharide 500 mg/mL
In Vitro: Human
coronary artery
endothelial cells
(HCAEC)
[28]
Peptides
Spirulina maxima
(Cyanobacteria/Cyanophyceae)
Anti-
atherosclerosis
Peptic
hydrolysates of
Spirulina
200 µM In Vitro: EA.hy926
endothelial cell [31]
Isochrysis zhanjiangensis
(Haptophyta/Coccolithophyceae)
Inhibit vascular
injury and
angiogenesis
Octapeptide
(IEC; Ile-Ile-Ala-
Val-Glu-Ala-Gly-
Cys)
1, 10, 20, and
50 µM
In Vitro: Human
umbilical vein
endothelial cells
(HUVECs)
[30]
Isochrysis zhanjiangensis
(Haptophyta/Coccolithophyceae)
Anti-hypertensive,
angiotensin-
converting enzyme
(ACE) inhibitors
Peptide (PIZ;
Phe-Glu-Ile-His-
Cys-Cys)
IC50 = 61.38 µM
In Vitro:
Hippuryl-His-Leu
(HHL) HHL assay
[36]
Chlamydomonas nivalis
(Chlorophyta/Chlorophyceae),
Porphyridium purpureum
(Rhodophyta/Porphyridiophyceae),
Chlorella vulgaris (Chloro-
phyta/Trebouxiophyceae),
Nannochloropsis gaditana
(Heterokonto-
phyta/Eustigmatophyceae), and
Scenedesmus sp.
(Chlorophyta/Chlorophyceae)
Angiotensin-
converting enzyme
(ACE) inhibitors
- 1 mg/mL
In Vitro:
Hippuryl-His-Leu
(HHL) HHL assay
[43]Mar. Drugs 2024, 22, 229 9 of 15
Table 1. Cont.
Microalgae Activity Observed Compound Conc. Model Reference
Chlorella vulgaris
(Chlorophyta/Trebouxiophyceae)
Anti-hypertensive,
angiotensin-
converting enzyme
(ACE) inhibitors
Water-soluble
hydrolysates rich
in pro-
teins/peptides
IC50: 286 µg
protein/mL
In Vitro:
Hippuryl-His-Leu
(HHL) HHL assay
[40]
Nannochloropsis oculate
(Heterokontophyta/
Eustigmatophyceae)
Angiotensin-
converting enzyme
(ACE) inhibitors
Peptides:
Gly-Met-Asn-
Asn-Leu-Thr-Pro
(GMNNLTP;
MW, 728 Da) and
Leu-Glu-Gln
(LEQ; MW, 369
Da),
IC50: 123
IC50 = 173 µM,
respectively
In Vitro:
Hippuryl-His-Leu
(HHL) HHL assay
[37]
Nitzschia laevis
(Heterokontophyta/
Bacillariophyceae)
Angiotensin-
converting enzyme
(ACE) inhibitors
-
IC50 = 1.63 ±
0.01 mg/mL
In Vitro:
Hippuryl-His-Leu
(HHL) HHL assay
[42]
Isochrysis galbana
(Haptophyta/Coccolithophyceae)
Angiotensin-
converting enzyme
(ACE) inhibitors
Peptide: (Tyr-
Met-Gly-Leu-
Asp-Leu-Lys)
IC50 = 36.1 µM
In Vitro:
Hippuryl-His-Leu
(HHL) HHL assay
[38]
Marine Spirulina sp.
(Cyanobacteria/Cyanophyceae)
Anti-hypertensive,
angiotensin-
converting enzyme
(ACE) inhibitors
Peptide
(Thr-Met-Glu-
Pro-Gly-Lys-Pro)
IC50 = 0.3 mg/mL
In Vitro:
Hippuryl-His-Leu
(HHL) HHL assay
[39]
Isochrysis zhanjiangensis
(Haptophyta/Coccolithophyceae)
Anti-
atherosclerosis,
anti-apoptosis and
anti-inflammation
Nonapeptide
named ETT
(Glu-Met-Phe-
Gly-Thr-Ser-
SerGlu-Thr)
IC50 = 15.08 µM
In Vitro:
Hippuryl-His-Leu
(HHL) HHL assay
[41]
Chlorella ellipsoidea
(Chlorophyta/Trebouxiophyceae)
Anti-hypertensive,
angiotensin-
converting enzyme
(ACE) inhibitors
Peptide (Val–Glu–
Gly–Tyr)
In Vitro:
IC50 = 128.4 µM
In Vivo:
10 mg/kg of
body weight
In Vitro:
Hippuryl-His-Leu
(HHL) HHL assay
In Vivo: Rats
[44]
Bellerochea malleus
(Heterokontophyta/Mediophyceae)
Anti-hypertensive,
ACE-inhibitory
activities,
Papain
hydrolysates
In Vitro:
2 mg m/L;
In Vivo: the
dose of
400 mg/kg
body weight
In Vitro:
Hippuryl-His-Leu
(HHL) HHL assay
In Vivo: Rats
[45]
Porphyridium sp.
(Rhodophyta/Porphyridiophyceae) Anti-hypertensive
Peptide:
GVDYVRFF,
AIPAAPAAPAG-
PKLY, and
LIHADPPGVGL
- In Vivo: Rats [46]
Carotenoids
Dunaliella
salina
(Chlorophyta/Chlorophyceae)
Ameliorate
age-associated
cardiac
dysfunction
Zeaxanthin
heneicosylate
(ZH)
250 µg/kg In Vivo: Rats [49]
Dunaliella
salina
(Chlorophyta/Chlorophyceae)
Improve cardiac
tissue fibrosis and
congestion in the
myocardial blood
vessels
Carotenoid rich
fraction
150 mg/kg
body weight In Vivo: Rats [50]Mar. Drugs 2024, 22, 229 10 of 15
Table 1. Cont.
Microalgae Activity Observed Compound Conc. Model Reference
Haematococcus pluvialis Antioxidant Astaxanthin 10 µg/mL
In Vitro: Human
endothelial cells
(HUVECs)
[48]
Dunaliella salina
Protective
potentials against
cardiac
dysfunction
Antioxidant
β-carotene rich
Dunaliella salina
carotenoid fraction
250 mg/kg In Vivo: Rats [53]
Dunaliella salina
(Chlorophyta/Chlorophyceae)
Improve
Myocardial
ischemia-
reperfusion injury
(MIRI),
improve left
ventricle function
and reduce the rate
of malignant
arrhythmia
- 500 mg/kg
Langendorff
perfused heart
model in mice
[51]
Chlorella sp.
(Chlorophyta/Trebouxiophyceae) Anti-hypertensive - 20 mg Clinical trials [64]
Spirulina platensis
(Cyanobacteria/Cyanophyceae) Anti-hypertensive - 2 g Clinical trials [65]
Lipids and other bioactive extracts and molecules
Nannochloropsis sp.
(Heterokontophyta/
Eustigmatophyceae)
Anti-
atherosclerosis
Lyso-
diacylglyceryltr-
imethylhomoserine
(lyso-DGTS)
1.43 mg/mL In Vivo: Mice [54]
A Mixture of Schizochytrium sp.
and Extra Virgin Olive Oils
(not found in algaebase, but
found in wikipedia)
Attenuate
aging-induced
endothelial
dysfunction
2.5 mL/kg of a
mixture of 75% of
EVOO (Cornicabra
variety; 80% oleic
acid and
63.49 mg/g of
secoiridoids) and
25% of Algae oil
(Schizochytrium
spp.: 35% DHA,
20% EPA and 5%
Docosapentaenoic
(DPA))
Omega-3
polyunsatu-
rated fatty
acids (ω-3
PUFA)
In Vivo: Male
Wistar rats [55]
Freeze-dried Odontella
aurita
(Heterokontophyta/Mediophyceae)
Anti-
atherosclerosis,
reduced
insulinemia, serum
lipid levels,
platelet
aggregation and
oxidative status
Marine omega-3
12% (w/w) of
freeze-dried
O. aurita
In Vivo: Male
Wistar
rats
[56]
Spirulina sp.
Cyanobacteria/Cyanophyceae)
Anti-
atherosclerosis
Dietary
silicon-enriched
Spirulina (SES)
Hamster on a
high-fat diet
were treated
with Spirulina
or SES at a
dose
57 mg/kg
body weight
daily,
In Vivo: Hamster [57,58]Mar. Drugs 2024, 22, 229 11 of 15
Table 1. Cont.
Microalgae Activity Observed Compound Conc. Model Reference
Spirulina platensis, Ganoderma
lucidum and Moringa oleifera
Reduction in
NLRP3 and
p65/NF-kB levels
in human
cardiomyocytes.
Reduction in
fibrosis and
hypertrophy in the
myocardial tissues
of mice
Singo (Spirulina
platensis,
Ganoderma lucidum
and Moringa
oleifera)
In Vitro: 10,
15 and
50 µg/mL
In Vivo:
12 mg/kg
In Vitro: Human
cardiomyocyte.
In Vivo: Mice
[59]
Dunaliella salina
Cardioprotective
effects against
myocardial is-
chemia/reperfusion
(I/R) injury
Dunaliella salina
extract 0.1 mg/kg In Vivo: Rats [61]
Euglena gracilis Improvement in
cardiac function
-
Euglena
gracilis 2% In Vivo: Mice [66]
Chlorella pyrenoidosa
Ameliorative
effects on CVDs
factors
-
15 g for
14 days Clinical trials [63]
Microchloropsis salina
Improvement in
fatty acid
distribution in
plasma lipids
-
15 g for
14 days Clinical trials [63]
Chlorella pyrenoidosa Anti-hypertensive - 40 mg/Kg In Vivo: Rats [62]
6. Conclusions
Overall, this review highlights that the most common compounds with bioactivities
useful for cardiovascular diseases are omega-3, pigments, peptides, and carbohydrates. The
most abundant phyla of microalgae that have shown beneficial activities for heart-related
diseases were Chlorophyta (i.e., Chlorella sp., Chlamydomonas nivalis, Chlorella vulgaris,
Chlorella ellipsoidea, Scenedesmus sp., Dunaliella salina), followed by Heterokontophyta and
Rhodophyta. In general, the most common mechanisms of action involved in the protective
role of microalgal extracts and compounds for cardiovascular diseases are antioxidant
and anti-inflammatory activity by reducing free radicals and inhibiting the release of
inflammatory mediators (Figure 2).
As regards patents, the WO2019026067A1 relates to extracts of the microalga Nan-
nochloropsis and their uses. According to the patent, the nutraceutical composition of
WO2019026067A1 (https://patents.google.com/patent/WO2019026067A1/en; accessed on
14 March 2024) may be used for ameliorating conditions associated with atherogenesis and
preventing atherosclerotic cardiovascular diseases and associated conditions, such as heart
attack, stroke, and high blood pressure. An example of a product is Spirulysat®, a product
produced by AlgoSource (https://algosource.com/healthcare/preventive-cardiovascular-
care/; accessed on 14 March 2024), based on Spirulina extracts, rich in phycocyanins.
AlgoSource suggests this product for cardiovascular disease prevention. In particular,
Spirulysat® was suggested to prevent the formation of atheroma plaques (https://algosource.
com/healthcare/preventive-cardiovascular-care/; accessed on 14 March 2024). Owing to
their rapid growth, the possibility of applying metabolic engineering, and multiple bioac-
tive metabolites, marine microalgae represent a great sustainable source of molecules for an
industry-scale production of ingredients for functional foods, cosmeceuticals and possible
future drugs.Mar. Drugs 2024, 22, 229 Mar. Drugs 2024, 22, 229 12 of 15
12 of 15
Figure 2. A schematic representation of microalgal bioactive molecules for different age-related car-
Figure 2. A schematic representation of microalgal bioactive molecules for different age-related
diovascular disease applications. CVD abbreviation stands for cardiovascular disease.
cardiovascular disease applications. CVD abbreviation stands for cardiovascular disease.
Author Contributions: Conceptualization, C.L.; writing—original draft preparation, N.Y., E.M. and
Author Contributions: Conceptualization, C.L.; writing—original draft preparation, N.Y., E.M. and
C.L.; writing—review and editing, N.Y., E.M. and C.L. All authors have read and agreed to the
C.L.; writing—review and editing, N.Y., E.M. and C.L. All authors have read and agreed to the
published version of the manuscript.
published version of the manuscript.
Funding: This research received no external funding.
Funding: This research received no external funding.
Acknowledgments: The authors thank Servier Medical Art (SMART; https://smart.servier.com/ ac-
Acknowledgments: The authors thank Servier Medical Art (SMART; https://smart.servier.com/
cessed on 5 March 2024) and the IAN/UMCES Symbol and Image Libraries (Integration and Appli-
accessed on 5 March 2024) and the IAN/UMCES Symbol and Image Libraries (Integration and
cation Network; ian.umces.edu/media-library accessed on 27 March 2024) for the element in Figures
Application Network; ian.umces.edu/media-library accessed on 27 March 2024) for the element in
1 and 2.
Figures 1 and 2.
Conflicts of Interest: The authors declare no conflict of interest.
Conflicts of Interest: The authors declare no conflict of interest.
References
References
1. 1. Montuori, E.; Capalbo, A.; Lauritano, C. Marine Compounds for Melanoma Treatment and Prevention. Int. J. Mol. Sci. 2022, 23,
Montuori, E.; Capalbo, A.; Lauritano, C. Marine Compounds for Melanoma Treatment and Prevention. Int. J. Mol. Sci.
10284. https://doi.org/10.3390/ijms231810284.
2022, 23, 10284. [CrossRef] [PubMed]
2. 2. Montuori, E.; Hyde, C.A.C.; Crea, F.; Golding, J.; Lauritano, C. Marine Natural Products with Activities against Prostate Cancer:
Montuori, E.; Hyde, C.A.C.; Crea, F.; Golding, J.; Lauritano, C. Marine Natural Products with Activities against Prostate Cancer:
Recent Discoveries. Int. J. Mol. Sci. 2023, 24, 1435. https://doi.org/10.3390/ijms24021435.
Recent Discoveries. Int. J. Mol. Sci. 2023, 24, 1435. [CrossRef]
3. 3. Saide, A.; Martínez, K.A.; Ianora, A.; Lauritano, C. Unlocking the Health Potential of Microalgae as Sustainable Sources of
Saide, A.; Martínez, K.A.; Ianora, A.; Lauritano, C. Unlocking the Health Potential of Microalgae as Sustainable Sources of
Bioactive Compounds. Int. J. Mol. Sci. 2021, 22, 4383. https://doi.org/10.3390/ijms22094383.
Bioactive Compounds. Int. J. Mol. Sci. 2021, 22, 4383. [CrossRef] [PubMed]
4. 4. Manson, J.E.; Cook, N.R.; Lee, I.-M.; Christen, W.; Bassuk, S.S.; Mora, S.; Gibson, H.; Albert, C.M.; Gordon, D.; Copeland, T.; et
Manson, J.E.; Cook, N.R.; Lee, I.-M.; Christen, W.; Bassuk, S.S.; Mora, S.; Gibson, H.; Albert, C.M.; Gordon, D.; Copeland, T.; et al.
al. Marine N−3 Fatty Acids and Prevention of Cardiovascular Disease and Cancer. N. Engl. J. Med. 2019, 380, 23–32.
Marine N−3 Fatty Acids and Prevention of Cardiovascular Disease and Cancer. N. Engl. J. Med. 2019, 380, 23–32. [CrossRef]
https://doi.org/10.1056/NEJMoa1811403.
[PubMed]5. Khan, S.U.; Lone, A.N.; Khan, M.S.; Virani, S.S.; Blumenthal, R.S.; Nasir, K.; Miller, M.; Michos, E.D.; Ballantyne, C.M.; Boden,
W.E.; et al. Effect of Omega-3 Fatty Acids on Cardiovascular Outcomes: A Systematic Review and Meta-Analysis. eClinicalMedi-
cine 2021, 38, 100997. https://doi.org/10.1016/j.eclinm.2021.100997.Mar. Drugs 2024, 22, 229 13 of 15
5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26. 27. 28. 29. 30. Khan, S.U.; Lone, A.N.; Khan, M.S.; Virani, S.S.; Blumenthal, R.S.; Nasir, K.; Miller, M.; Michos, E.D.; Ballantyne, C.M.; Boden, W.E.;
et al. Effect of Omega-3 Fatty Acids on Cardiovascular Outcomes: A Systematic Review and Meta-Analysis. eClinicalMedicine
2021, 38, 100997. [CrossRef] [PubMed]
Sherratt, S.C.R.; Libby, P.; Budoff, M.J.; Bhatt, D.L.; Mason, R.P. Role of Omega-3 Fatty Acids in Cardiovascular Disease: The
Debate Continues. Curr. Atheroscler. Rep. 2023, 25, 1–17. [CrossRef] [PubMed]
Marhuenda, J.; Villaño, D.; Cerdá, B.; Pilar Zafrilla, M. Cardiovascular Disease and Nutrition. In Nutrition in Health and Disease—Our
Challenges Now and Forthcoming Time; Mózsik, G., Figler, M., Eds.; IntechOpen: London, UK, 2019; ISBN 978-1-78984-007-0.
Albracht-Schulte, K.; Kalupahana, N.S.; Ramalingam, L.; Wang, S.; Rahman, S.M.; Robert-McComb, J.; Moustaid-Moussa, N.
Omega-3 Fatty Acids in Obesity and Metabolic Syndrome: A Mechanistic Update. J. Nutr. Biochem. 2018, 58, 1–16. [CrossRef]
[PubMed]
EFSA Panel on Dietetic Products, Nutrition, and Allergies (NDA). Scientific Opinion on Dietary Reference Values for Fats,
Including Saturated Fatty Acids, Polyunsaturated Fatty Acids, Monounsaturated Fatty Acids, Trans Fatty Acids, and Cholesterol.
EFSA J. 2010, 8, 1461. [CrossRef]
Lauritano, C.; Montuori, E.; De Falco, G.; Carrella, S. In Silico Methodologies to Improve Antioxidants’ Characterization from
Marine Organisms. Antioxidants 2023, 12, 710. [CrossRef] [PubMed]
Fisher, M.; Lees, K.; Spence, J.D. Nutrition and Stroke Prevention. Stroke 2006, 37, 2430–2435. [CrossRef]
Raposo, M.F.D.J.; De Morais, A.M.M.B. Microalgae for the Prevention of Cardiovascular Disease and Stroke. Life Sci. 2015, 125,
32–41. [CrossRef] [PubMed]
Plotnick, G.D.; Corretti, M.C.; Vogel, R.A. Effect of Antioxidant Vitamins on the Transient Impairment of Endothelium-Dependent
Brachial Artery Vasoactivity Following a Single High-Fat Meal. JAMA 1997, 278, 1682–1686. [CrossRef]
Prince, M.J.; Wu, F.; Guo, Y.; Gutierrez Robledo, L.M.; O’Donnell, M.; Sullivan, R.; Yusuf, S. The Burden of Disease in Older People
and Implications for Health Policy and Practice. Lancet 2015, 385, 549–562. [CrossRef] [PubMed]
Lakatta, E.G. Age-Associated Cardiovascular Changes in Health: Impact on Cardiovascular Disease in Older Persons. Heart Fail.
Rev. 2002, 7, 29–49. [CrossRef]
Sleeman, K.E.; De Brito, M.; Etkind, S.; Nkhoma, K.; Guo, P.; Higginson, I.J.; Gomes, B.; Harding, R. The Escalating Global Burden
of Serious Health-Related Suffering: Projections to 2060 by World Regions, Age Groups, and Health Conditions. Lancet Glob.
Health 2019, 7, e883–e892. [CrossRef] [PubMed]
Lettino, M.; Mascherbauer, J.; Nordaby, M.; Ziegler, A.; Collet, J.P.; Derumeaux, G.; Hohnloser, S.H.; Leclercq, C.; O’Neill, D.E.;
Visseren, F.; et al. Cardiovascular Disease in the Elderly: Proceedings of the European Society of Cardiology—Cardiovascular
Round Table. Eur. J. Prev. Cardiol. 2022, 29, 1412–1424. [CrossRef] [PubMed]
Adhikary, D.; Barman, S.; Ranjan, R.; Stone, H. A Systematic Review of Major Cardiovascular Risk Factors: A Growing Global
Health Concern. Cureus 2022, 14, e30119. [CrossRef] [PubMed]
Izzo, C.; Carrizzo, A.; Alfano, A.; Virtuoso, N.; Capunzo, M.; Calabrese, M.; De Simone, E.; Sciarretta, S.; Frati, G.; Oliveti, M.;
et al. The Impact of Aging on Cardio and Cerebrovascular Diseases. Int. J. Mol. Sci. 2018, 19, 481. [CrossRef]
Gao, Z.; Chen, Z.; Sun, A.; Deng, X. Gender Differences in Cardiovascular Disease. Med. Nov. Technol. Devices 2019, 4, 100025.
[CrossRef]
Nadeem, M.; Ahmed, S.S.; Mansoor, S.; Farooq, S. Risk Factors for Coronary Heart Disease in Patients below 45 Years of Age. Pak.
J. Med. Sci. 2012, 29, 91–96. [CrossRef]
Tuomilehto, J. Impact of Age on Cardiovascular Risk: Implications for Cardiovascular Disease Management. Atheroscler. Suppl.
2004, 5, 9–17. [CrossRef] [PubMed]
Rodgers, J.L.; Jones, J.; Bolleddu, S.I.; Vanthenapalli, S.; Rodgers, L.E.; Shah, K.; Karia, K.; Panguluri, S.K. Cardiovascular Risks
Associated with Gender and Aging. J. Cardiovasc. Dev. Dis. 2019, 6, 19. [CrossRef] [PubMed]
Ciumărnean, L.; Milaciu, M.V.; Negrean, V.; Orăs
, an, O.H.; Vesa, S.C.; Sălăgean, O.; Ilu¸t, S.; Vlaicu, S.I. Cardiovascular Risk Factors
and Physical Activity for the Prevention of Cardiovascular Diseases in the Elderly. Int. J. Environ. Res. Public Health 2021, 19, 207.
[CrossRef] [PubMed]
Singam, N.S.V.; Fine, C.; Fleg, J.L. Cardiac Changes Associated with Vascular Aging. Clin. Cardiol. 2020, 43, 92–98. [CrossRef]
[PubMed]
El Assar, M.; Angulo, J.; Vallejo, S.; Peiró, C.; Sánchez-Ferrer, C.F.; Rodríguez-Mañas, L. Mechanisms Involved in the Aging-
Induced Vascular Dysfunction. Front. Physiol. 2012, 3, 132. [CrossRef] [PubMed]
Levy-Ontman, O.; Huleihel, M.; Hamias, R.; Wolak, T.; Paran, E. An Anti-Inflammatory Effect of Red Microalga Polysaccharides
in Coronary Artery Endothelial Cells. Atherosclerosis 2017, 264, 11–18. [CrossRef] [PubMed]
Hamias, R.; Wolak, T.; Huleihel, M.; Paran, E.; Levy-Ontman, O. Red Alga Polysaccharides Attenuate Angiotensin II-Induced
Inflammation in Coronary Endothelial Cells. Biochem. Biophys. Res. Commun. 2018, 500, 944–951. [CrossRef]
Li, Y.; Lammi, C.; Boschin, G.; Arnoldi, A.; Aiello, G. Recent Advances in Microalgae Peptides: Cardiovascular Health Benefits
and Analysis. J. Agric. Food Chem. 2019, 67, 11825–11838. [CrossRef] [PubMed]
Lin, L.; He, Y.-L.; Tang, Y.; Hong, P.; Zhou, C.; Sun, S.; Qian, Z.-J. Mechanism Analysis of Octapeptide from Microalgae, Isochrysis
zhanjiangensis for Suppressing Vascular Injury and Angiogenesis in Human Umbilical Vein Endothelial Cell. Int. Immunopharmacol.
2022, 111, 109149. [CrossRef]Mar. Drugs 2024, 22, 229 14 of 15
31. 32. 33. 34. 35. 36. 37. 38. 39. 40. 41. 42. 43. 44. 45. 46. 47. 48. 49. 50. 51. 52. 53. 54. Vo, T.-S.; Ryu, B.; Kim, S.-K. Purification of Novel Anti-Inflammatory Peptides from Enzymatic Hydrolysate of the Edible
Microalgal Spirulina maxima. J. Funct. Foods 2013, 5, 1336–1346. [CrossRef]
Jiang, Q.; Chen, Q.; Zhang, T.; Liu, M.; Duan, S.; Sun, X. The Antihypertensive Effects and Potential Molecular Mechanism of
Microalgal Angiotensin I-Converting Enzyme Inhibitor-Like Peptides: A Mini Review. Int. J. Mol. Sci. 2021, 22, 4068. [CrossRef]
[PubMed]
Giles, T.D.; Materson, B.J.; Cohn, J.N.; Kostis, J.B. Definition and Classification of Hypertension: An Update. J. Clin. Hypertens.
2009, 11, 611–614. [CrossRef]
Van Thiel, B.S.; Van Der Pluijm, I.; Te Riet, L.; Essers, J.; Danser, A.H.J. The Renin–Angiotensin System and Its Involvement in
Vascular Disease. Eur. J. Pharmacol. 2015, 763, 3–14. [CrossRef]
Li, E.C.; Heran, B.S.; Wright, J.M. Angiotensin Converting Enzyme (ACE) Inhibitors versus Angiotensin Receptor Blockers for
Primary Hypertension. Cochrane Database Syst. Rev. 2014, 2014, CD009096. [CrossRef]
Chen, L.; Giesy, J.P.; Adamovsky, O.; Svirˇcev, Z.; Meriluoto, J.; Codd, G.A.; Mijovic, B.; Shi, T.; Tuo, X.; Li, S.-C.; et al. Challenges of
Using Blooms of Microcystis spp. in Animal Feeds: A Comprehensive Review of Nutritional, Toxicological and Microbial Health
Evaluation. Sci. Total Environ. 2021, 764, 142319. [CrossRef]
Samarakoon, K.W.; O-Nam, K.; Ko, J.-Y.; Lee, J.-H.; Kang, M.-C.; Kim, D.; Lee, J.B.; Lee, J.-S.; Jeon, Y.-J. Purification and Identifica-
tion of Novel Angiotensin-I Converting Enzyme (ACE) Inhibitory Peptides from Cultured Marine Microalgae (Nannochloropsis
oculata) Protein Hydrolysate. J. Appl. Phycol. 2013, 25, 1595–1606. [CrossRef]
Wu, H.; Xu, N.; Sun, X.; Yu, H.; Zhou, C. Hydrolysis and Purification of ACE Inhibitory Peptides from the Marine Microalga
Isochrysis galbana. J. Appl. Phycol. 2015, 27, 351–361. [CrossRef]
Heo, S.-J.; Yoon, W.-J.; Kim, K.-N.; Oh, C.; Choi, Y.-U.; Yoon, K.-T.; Kang, D.-H.; Qian, Z.-J.; Choi, I.-W.; Jung, W.-K. Anti-
Inflammatory Effect of Fucoxanthin Derivatives Isolated from Sargassum siliquastrum in Lipopolysaccharide-Stimulated RAW
264.7 Macrophage. Food Chem. Toxicol. 2012, 50, 3336–3342. [CrossRef]
Cunha, S.A.; Coscueta, E.R.; Nova, P.; Silva, J.L.; Pintado, M.M. Bioactive Hydrolysates from Chlorella vulgaris: Optimal Process
and Bioactive Properties. Molecules 2022, 27, 2505. [CrossRef]
Pei, Y.; Lui, Y.; Cai, S.; Zhou, C.; Hong, P.; Qian, Z.-J. A Novel Peptide Isolated from Microalgae Isochrysis zhanjiangensis Exhibits
Anti-Apoptosis and Anti-Inflammation in Ox-LDL Induced HUVEC to Improve Atherosclerosis. Plant Foods Hum. Nutr. 2022, 77,
181–189. [CrossRef]
Alzahrani, M.A.J. Proteins and Their Enzymatic Hydrolysates from the Marine Diatom Nitzschia laevis and Screening for Their In
Vitro Antioxidant, Antihypertension, Anti-Inflammatory and Antimicrobial Activities. Ph.D. Thesis, University of Auckland,
Auckland, New Zealand, 2018. [CrossRef]
Verspreet, J.; Soetemans, L.; Gargan, C.; Hayes, M.; Bastiaens, L. Nutritional Profiling and Preliminary Bioactivity Screening of
Five Micro-Algae Strains Cultivated in Northwest Europe. Foods 2021, 10, 1516. [CrossRef]
Ko, S.-C.; Kang, N.; Kim, E.-A.; Kang, M.C.; Lee, S.-H.; Kang, S.-M.; Lee, J.-B.; Jeon, B.-T.; Kim, S.-K.; Park, S.-J.; et al. A Novel
Angiotensin I-Converting Enzyme (ACE) Inhibitory Peptide from a Marine Chlorella ellipsoidea and Its Antihypertensive Effect in
Spontaneously Hypertensive Rats. Process Biochem. 2012, 47, 2005–2011. [CrossRef]
Barkia, I.; Al-Haj, L.; Abdul Hamid, A.; Zakaria, M.; Saari, N.; Zadjali, F. Indigenous Marine Diatoms as Novel Sources of
Bioactive Peptides with Antihypertensive and Antioxidant Properties. Int. J. Food Sci. Technol. 2019, 54, 1514–1522. [CrossRef]
Hayes, M.; Aluko, R.E.; Aurino, E.; Mora, L. Generation of Bioactive Peptides from Porphyridium sp. and Assessment of Their
Potential for Use in the Prevention of Hypertension, Inflammation and Pain. Mar. Drugs 2023, 21, 422. [CrossRef] [PubMed]
Zuluaga, M.; Gueguen, V.; Letourneur, D.; Pavon-Djavid, G. Astaxanthin-Antioxidant Impact on Excessive Reactive Oxygen
Species Generation Induced by Ischemia and Reperfusion Injury. Chem.-Biol. Interact. 2018, 279, 145–158. [CrossRef] [PubMed]
Cutrell, S.; Alhomoud, I.S.; Mehta, A.; Talasaz, A.H.; Van Tassell, B.; Dixon, D.L. ACE-Inhibitors in Hypertension: A Historical
Perspective and Current Insights. Curr. Hypertens. Rep. 2023, 25, 243–250. [CrossRef] [PubMed]
El-Baz, F.; Abdel Jaleel, G.; Saleh, D.; Hussein, R. Protective and Therapeutic Potentials of Dunaliella salina on Aging-Associated
Cardiac Dysfunction in Rats. Asian Pac. J. Trop. Biomed. 2018, 8, 403. [CrossRef]
El-Baz, F.K.; Hussein, R.A.; Saleh, D.O.; Abdel Jaleel, G.A.R. Zeaxanthin Isolated from Dunaliella salina Microalgae Ameliorates
Age Associated Cardiac Dysfunction in Rats through Stimulation of Retinoid Receptors. Mar. Drugs 2019, 17, 290. [CrossRef]
[PubMed]
Song, J.; Li, H.; Zhang, Y.; Wang, T.; Dong, Y.; Shui, H.; Du, J. Effect of Dunaliella salina on Myocardial Ischemia-Reperfusion Injury
through KEAP1/NRF2 Pathway Activation and JAK2/STAT3 Pathway Inhibition. Gene Protein Dis. 2023, 2, 387. [CrossRef]
Da Silva, F.; Jian Motamedi, F.; Weerasinghe Arachchige, L.C.; Tison, A.; Bradford, S.T.; Lefebvre, J.; Dolle, P.; Ghyselinck, N.B.;
Wagner, K.D.; Schedl, A. Retinoic Acid Signaling Is Directly Activated in Cardiomyocytes and Protects Mouse Hearts from
Apoptosis after Myocardial Infarction. eLife 2021, 10, e68280. [CrossRef]
El-Baz, F.K.; Aly, H.F.; Abd-Alla, H.I. The Ameliorating Effect of Carotenoid Rich Fraction Extracted from Dunaliella salina
Microalga against Inflammation- Associated Cardiac Dysfunction in Obese Rats. Toxicol. Rep. 2020, 7, 118–124. [CrossRef]
Dahli, L.; Atrahimovich, D.; Vaya, J.; Khatib, S. Lyso-DGTS Lipid Isolated from Microalgae Enhances PON1 Activities In
Vitro and In Vivo, Increases PON1 Penetration into Macrophages and Decreases Cellular Lipid Accumulation. BioFactors
2018, 44, 299–310. [CrossRef] [PubMed]Mar. Drugs 2024, 22, 229 15 of 15
55. 56. 57. 58. 59. 60. 61. 62. 63. 64. 65. 66. González-Hedström, D.; Amor, S.; De La Fuente-Fernández, M.; Tejera-Muñoz, A.; Priego, T.; Martín, A.I.; López-Calderón,
A.; Inarejos-García, A.M.; García-Villalón, Á.L.; Granado, M. A Mixture of Algae and Extra Virgin Olive Oils Attenuates the
Cardiometabolic Alterations Associated with Aging in Male Wistar Rats. Antioxidants 2020, 9, 483. [CrossRef]
Haimeur, A.; Ulmann, L.; Mimouni, V.; Guéno, F.; Pineau-Vincent, F.; Meskini, N.; Tremblin, G. The Role of Odontella aurita, a
Marine Diatom Rich in EPA, as a Dietary Supplement in Dyslipidemia, Platelet Function and Oxidative Stress in High-Fat Fed
Rats. Lipids Health Dis. 2012, 11, 147. [CrossRef] [PubMed]
Dudek, Ł.; Kochman, W.; Dziedzic, E. Silicon in Prevention of Atherosclerosis and Other Age-Related Diseases. Front. Cardiovasc.
Med. 2024, 11, 1370536. [CrossRef] [PubMed]
Vidé, J.; Virsolvy, A.; Romain, C.; Ramos, J.; Jouy, N.; Richard, S.; Cristol, J.-P.; Gaillet, S.; Rouanet, J.-M. Dietary Silicon-Enriched
Spirulina Improves Early Atherosclerosis Markers in Hamsters on a High-Fat Diet. Nutrition 2015, 31, 1148–1154. [CrossRef]
Quagliariello, V.; Basilicata, M.G.; Pepe, G.; De Anseris, R.; Di Mauro, A.; Scognamiglio, G.; Palma, G.; Vestuto, V.; Buccolo, S.;
Luciano, A.; et al. Combination of Spirulina platensis, Ganoderma lucidum and Moringa oleifera Improves Cardiac Functions and
Reduces Pro-Inflammatory Biomarkers in Preclinical Models of Short-Term Doxorubicin-Mediated Cardiotoxicity: New Frontiers
in Cardioncology? J. Cardiovasc. Dev. Dis. 2022, 9, 423. [CrossRef]
Umei, M.; Akazawa, H.; Saga-Kamo, A.; Yagi, H.; Liu, Q.; Matsuoka, R.; Kadowaki, H.; Shindo, A.; Nakashima, A.; Yasuda,
K.; et al. Oral Administration of Euglena gracilis Z Alleviates Constipation and Cardiac Dysfunction in a Mouse Model of
Isoproterenol-Induced Heart Failure. Circ. Rep. 2022, 4, 83–91. [CrossRef]
Tsai, C.-F.; Lin, H.-W.; Liao, J.-M.; Chen, K.-M.; Tsai, J.-W.; Chang, C.-S.; Chou, C.-Y.; Su, H.-H.; Liu, P.-H.; Chu, Y.-C.; et al.
Dunaliella salina Alga Protects against Myocardial Ischemia/Reperfusion Injury by Attenuating TLR4 Signaling. Int. J. Mol. Sci.
2023, 24, 3871. [CrossRef]
Yang, S.-C.; Yang, H.-Y.; Yang, Y.-C.; Peng, H.-C.; Ho, P.-Y. Chlorella pyrenoidosa Ameliorated L-NAME-Induced Hypertension and
Cardiorenal Remodeling in Rats. Eur. J. Nutr. 2013, 52, 601–608. [CrossRef]
Sandgruber, F.; Höger, A.-L.; Kunze, J.; Schenz, B.; Griehl, C.; Kiehntopf, M.; Kipp, K.; Kühn, J.; Stangl, G.I.; Lorkowski, S.;
et al. Impact of Regular Intake of Microalgae on Nutrient Supply and Cardiovascular Risk Factors: Results from the NovAL
Intervention Study. Nutrients 2023, 15, 1645. [CrossRef] [PubMed]
Shimada, M.; Hasegawa, T.; Nishimura, C.; Kan, H.; Kanno, T.; Nakamura, T.; Matsubayashi, T. Anti-Hypertensive Effect of
γ-Aminobutyric Acid (GABA)-Rich Chlorella on High-Normal Blood Pressure and Borderline Hypertension in Placebo-Controlled
Double Blind Study. Clin. Exp. Hypertens. 2009, 31, 342–354. [CrossRef] [PubMed]
Ghaem Far, Z.; Babajafari, S.; Kojuri, J.; Mohammadi, S.; Nouri, M.; Rostamizadeh, P.; Rahmani, M.H.; Azadian, M.; Ashrafi-
Dehkordi, E.; Zareifard, A.; et al. Antihypertensive and Antihyperlipemic of Spirulina (Arthrospira platensis) Sauce on Patients
with Hypertension: A Randomized Triple-blind Placebo-controlled Clinical Trial. Phytother. Res. 2021, 35, 6181–6190. [CrossRef]
AlKahtane, A.A.; Abushouk, A.I.; Mohammed, E.T.; ALNasser, M.; Alarifi, S.; Ali, D.; Alessia, M.S.; Almeer, R.S.; AlBasher, G.;
Alkahtani, S.; et al. Fucoidan Alleviates Microcystin-LR-Induced Hepatic, Renal, and Cardiac Oxidative Stress and Inflammatory
Injuries in Mice. Environ. Sci. Pollut. Res. 2020, 27, 2935–2944. [CrossRef] [PubMed]
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